Mortality and morbidity due to human immunodeficiency virus (HIV) infection has decreased due to antiretroviral therapy resulting in an aging population with chronic diseases. One of these illnesses is HIV-associated dementia (HAD), which we have observed in the Hawaii Aging with HIV Cohort. Preliminary data from our cohort reveals that HAD is almost twice as likely to occur in older (>50 year old) than in younger (20-40 year old) individuals. The etiology of dementias has been hypothesized to be due to neuronal injury induced by neurotoxic substances and inflammatory cytokines produced by activated monocytes/macrophages (M/Mo). We will utilize our neurocognitively well-characterized cohort (N=288) of older and younger HIV+ individuals to assess whether age-related alterations in macrophage activation and/or function partially explain the increased risk of dementia in older HIV+ individuals and to explore the role that HIV proviral integration plays in this process. Our hypothesis is that the increase in HAD in the older HIV seropositive patients is due to the activation of peripheral M/Mo possibly due to HIV proviral integration and in the secretion of neurotoxic factors and inflammatory cytokines. M/Mo will be obtained from 50 older and 50 younger patients with/without HAD; and CD 14/CD 16/CD69 activated markers will be quantitated; gene expression of TNF-alpha, IL-6, I1-8, FAS, and MCP-1 will be examined; and proviral integration of HIV will be determined. This work is significant because of the need for a better understanding of the interplay between the aging process, macrophage immune function and the direct and indirect effects of HIV infection on dementia in our aging HIV population. This work may lead to the identification of markers linked to the development of HAD and improve preventive and therapeutic strategies for HAD. Through the Exploratory/Developmental Grant (R21) Program, the proposed study will generate data upon which future studies in the area of HIV, aging, and HAD can be built. The pathogenic process associated with aging may synergistically impact the incidence of HAD in the older HIV+ population, therefore the data from this research will contribute information to the immunological aspect of HIV, aging and HAD.